IMED 7170
ALS-FTD
C9orf72
Healthy function
Hexanucleotide Repeat Expansion (HRE)
Pathogenic Mechanisms
Treatments
In the Clinic
Future Directions
Complex disease of motor neurons
Muscle and cognitive impairment
Familial and sporadic
Numerous molecular factors influence expression
Second most common form of pre-senile dementia
Frontal lobe degeneration and behavioral abnormalities
Familial and sporadic
Numerous molecular factors influence expression
Considerable clinical overlap
Shared Molecular Signatures / biomarkers
“Spectrum”
Why C9orf72?
Gene Structure
Isoforms
Normal Gene Function
Distribution in the body
Structure
Variable Repeat Numbers
Incomplete Penetrance
Variable Expressivity
Somatic Instability
Repeat Contraction
Hypermethylation
Dysregulated C9orf72 function
Immune phenotypes
Additive Effects
G-quadruplex structure
Sequester RNA-binding proteins
Frontal Cortex (FTD) and Spinal Cord (ALS)
Nucleolar stress
Repeat-associated non-ATG (RAN) translation
Different DPRs = Different mechanisms
Selective Neuronal Vulnerability
TDP-43
p62
TBK1
Antisense oligonucleotides (ASOs)
Small Molecule
Gene Therapy?
Timing and location
Diagnosis
Prognosis
Issues
Contribution of molecular mechanisms
Complex “interactome”
Familial vs. sporadic